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    Summary
    EudraCT Number:2018-003518-41
    Sponsor's Protocol Code Number:2018-4765
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-26
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-003518-41
    A.3Full title of the trial
    Efficacy of Diltiazem to improve coronary microvascular dysfunction: A randomized clinical trial
    De effectiviteit van Diltiazem om coronaire microvasculaire dysfunctie te verbeteren: een gerandomiseerd klinisch onderzoek (EDIT-CMD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Diltiazem to improve the function of the coronary arteries
    Effect van Diltiazem op het verbeteren van de functie van de kransslagaders van het hart
    A.3.2Name or abbreviated title of the trial where available
    EDIT-CMD
    A.4.1Sponsor's protocol code number2018-4765
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRadboudumc
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAbbott Vascular Netherlands B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboudumc
    B.5.2Functional name of contact pointResearch Cardiology Department
    B.5.3 Address:
    B.5.3.1Street AddressGeert Groteplein Zuid
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6500 HB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031243616785
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Diltiazem HCl retard
    D.2.1.1.2Name of the Marketing Authorisation holderApotex Europe BV
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDiltiazem HCl retard
    D.3.2Product code RVG 18594
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Coronary Microvascular Dysfunction (CMD). In CMD, ischemia is caused by impaired endothelial and/or non-endothelial coronary vasoreactivity resulting in the coronary microvasculature not dilating properly or becoming vasospastic.
    E.1.1.1Medical condition in easily understood language
    In coronary microvascular dysfunction (CMD), the small vessels that provide blood and oxygen to the heart muscle do not function properly. In some cases they cannot relax, in other cases they spasm.
    Bij patiënten met CMD functioneren de kleine kransslagaders die de hartspier van bloed voorzien niet goed. Soms kunnen de vaten zich niet goed ontspannen, of soms verkrampen ze juist.
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the effect of diltiazem on coronary microvascular function in patients with chronic angina and evidence of coronary microvascular dysfunction.
    E.2.2Secondary objectives of the trial
    To assess the effect of 6 weeks of treatment with diltiazem on the individual coronary function parameters in patients with coronary microvascular dysfunction.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients above the age of 18.
    2. Patients with chronic angina, defined as symptoms of angina at least 2 times a week despite medical therapy for the last 3 months.
    3. No signs of obstructive coronary artery disease (CAD), documented within 5 years* before inclusion by one of the following modalities:
    a. Coronary angiography: patients with non-obstructive (<50% stenosis) coronary arteries are eligible, or patients with intermediate stenosis (between 50 and 70%) with documented FFR >0.80 or iFR >0.89 on angiogram. In patients with a history of stenting are eligible if they have no current significant coronary epicardial stenoses, a minimum diameter stenosis of <10% is required.
    b. Coronary computed tomography angiography (CCTA) with finding of non-obstructive coronary arteries
    4. Baseline coronary functiontesting with at least one of the following:
    a. CFR ≤ 2.0
    b. IMR ≥ 25
    c. Abnormal acetylcholine test defined as the presence of (recognizable) angina, ischemic ECG abnormalities with or without epicardial spasm
    5. Signed written informed consent
    E.4Principal exclusion criteria
    1. Other cause of angina deemed highly likely by the treating physician.
    2. Active use of calcium channel blockers or any use of calcium channel blockers in the previous two weeks or known intolerance for non-dihydropyridine calcium channel blockers.
    3. Left ventricular ejection fraction < 50%.
    4. Recent PCI within the past 3 months.
    5. Patients with history of coronary artery bypass grafting (CABG).
    6. Surgically uncorrected significant congenital or valvular heart disease, cardiomyopathy or myocarditis.
    7. Significant renal impairment (eGFR < 30).
    8. Significant hepatic impairment (history or cirrhosis or abnormal serum ALT or AST 3-fold greater than the upper limit of normal).
    9. Pregnant women or women of child bearing potential who are planning to become pregnant within the next 3 months.
    10. Prior non-cardiac illness with an estimated life expectancy < 1 year.
    11. Contra-indication to coronary function testing:
    a. Contraindication or known hypersensitivity to adenosine.
    b. Contraindication or known hypersensitivity to acetylcholine.
    c. Contraindication to aminophylline.
    d. Ongoing dipyridamole treatment.
    12. Contra-indication for treatment with CCB: second or third degree AV block, sinus node dysfunction and/or bradycardia (heart rate < 40 beats/minute)
    13. Symptomatic hypotension or systolic BP < 100 mmHg at screening visit on 2 consecutive measurements.
    14. History of hospitalization for asthma and/or current use of ≥ 2 types of pulmonary medications for asthma and/or severe COPD with FEV1 < 50% of predicted.
    15.Participation in another clinical study with an IMP during the last month prior to enrolment.
    16. Inability of the patient, in the opinion of the investigator, to understand and/or comply with study medications, procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study.
    17. Unable to give informed consent (i.e. due to language barrier).
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients having a successful treatment with diltiazem, defined as normalization of at least one abnormal parameter
    A normal IMR is specified as IMR < 25, a normal CFR being a CFR > 2 and a normal acetylcholine test is specified as one without ECG abnormalities and without (recognizable) angina signs of spasm at the same acetylcholine dose used at baseline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 6 weeks of treatment with the IMP
    E.5.2Secondary end point(s)
    Change in the different parameters of the coronary function test (change in IMR, CFR, acetylcholine test parameters and absolute coronary blood flow).
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6 weeks of treatment with the IMP
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study may be terminated if the study procedures are not being performed according to GCP and/or if patients are placed at undue risk because of clinically relevant findings.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state142
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 142
    F.4.2.2In the whole clinical trial 142
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After a subject ends his/her participation in the trial, normal treatment for CMD will be continued.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-24
    P. End of Trial
    P.End of Trial StatusOngoing
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